6-substituted sulfonyl azabicyclo[3.2.1]octanes useful to inhibit 11β-hydroxysteroid dehydrogenase type-I

ABSTRACT

In its many embodiments, the present invention relates to a novel class of 6-substituted sulfonyl-1,3,3-trialkyl-6-azabicyclo[3.2.1]octane compounds useful to inhibit 11β-hydroxysteroid dehydrogenase type-I, pharmaceutical compositions containing the compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more conditions associated with the expression of 11β-hydroxysteroid dehydrogenase type-I using such compounds or pharmaceutical compositions.

RELATED APPLICATIONS

This application claims benefit of provisional application U.S. Ser. No.60/955,985, filed Aug. 15, 2007, herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates 6-substitutedsulfonyl-1,3,3-trialkyl-6-azabicyclo[3.2.1]octane compounds useful toinhibit 11β-hydroxysteroid dehydrogenase type-I, pharmaceuticalcompositions containing the compounds, and methods of treatment,prevention, inhibition, or amelioration of one or more conditionsassociated with the expression of 11β-hydroxysteroid dehydrogenasetype-I using such compounds or pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Glucocorticoids are steroid hormones that regulate many metabolic andhomeostatic processes, including fat metabolism, function anddistribution. Glucocorticoids also have profound and diversephysiological effects on development, neurobiology, inflammation, bloodpressure, metabolism and programmed cell death.

Glucocorticoid action is dependent on the following factors: 1)circulating levels of glucocorticoid; 2) protein binding ofglucocorticoids in circulation; 3) intracellular receptor density insidetarget tissues; and 4) tissue-specific pre-receptor metabolism byglucocorticoid-activating and glucocorticoid-inactivating enzymescollectively known as 11-beta-hydroxysteroid dehydrogenase (11-β-HSD).Two distinct isozymes of 11-β-HSD have been cloned and characterized.These two isozymes, known as 11-β-HSD type I and 11-β-HSD type II,respectively, catalyze the interconversion of active and inactive formsof various glucocorticoids. For example, in humans, the primaryendogenously-produced glucocorticoid is cortisol. 11-β-HSD type I and11-β-HSD type II catalyze the interconversion of hormonally activecortisol and inactive cortisone. 11-β-HSD type I is widely distributedin human tissues and its expression has been detected in lung, testis,central nervous system and most abundantly in liver and adipose tissue.Conversely, 11-β-HSD type II expression is found mainly in kidney,placenta, colon and salivary gland tissue.

Up-regulation of 11-β-HSD type I can lead to elevated cellularglucocorticoid levels and amplified glucocorticoid activity. This, inturn, can lead to increased hepatic glucose production, adipocytedifferentiation and insulin resistance. In type II diabetes, insulinresistance is a significant pathogenic factor in the development ofhyperglycemia. Persistent or uncontrolled hyperglycemia in both type 1and type 2 diabetes has been associated with increased incidence ofmacrovascular and/or microvascular complications includingatherosclerosis, coronary heart disease, peripheral vascular disease,stroke, nephropathy, neuropathy and retinopathy. Insulin resistance,even in the absence of profound hyperglycemia, is a component also ofmetabolic syndrome, which is characterized by elevated blood pressure,high fasting blood glucose levels, abdominal obesity, increasedtriglyceride levels and/or decreased HDL cholesterol. Further,glucocorticoids are known to inhibit the glucose-stimulated secretion ofinsulin from pancreatic beta-cells. Inhibition of 11-β-HSD type I is,therefore, expected to be beneficial in the treatment of metabolicsyndromes, obesity, obesity-related disorders, hypertension,atherosclerosis, lipid disorders, type-II diabetes, insulin resistance,pancreatitis and associated conditions.

Mild cognitive impairment is a common feature of aging that may beultimately related to the progression of dementia. Chronic exposure toglucocorticoid excess in certain brain subregions has been proposed tocontribute to the decline of cognitive function. Inhibition of 11-β-HSDtype I is expected to reduce exposure to glucocorticoids in the brainand protect against deleterious glucocorticoid effects on neuronalfunction, including cognitive impairment, dementia and/or depression,especially in connection with Alzheimer's Disease.

Glucocorticoids also have a role in corticosteroid-induced glaucoma.This particular pathology is characterized by a significant increase inintra-ocular pressure, which unresolved can lead to partial visual fieldloss and eventually blindness. Inhibition of 11-β-HSD type I is expectedto reduce local glucocorticoid concentrations and, thus, intra-ocularpressure, producing beneficial effects in the management of glaucoma andother visual disorders.

Finally, glucocorticoids can have adverse effects on skeletal tissues.Continued exposure to excess glucocorticoids can produce osteoporosisand increased risk of fractures. Inhibition of 11-β-HSD type I shouldreduce local glucocorticoid concentration within osteoblasts andosteoclasts, producing beneficial effects for management of bonedisease, including osteoporosis.

In view of the foregoing, there is a clear and continuing need for newcompounds that target 11-β-HSD type I.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class ofheterocyclic compounds as inhibitors of 11β-hydroxysteroid dehydrogenasetype-I, pharmaceutical compositions containing the compounds, andmethods of treatment, prevention, inhibition, or amelioration of one ormore conditions associated with the expression of 11β-hydroxysteroiddehydrogenase type-I using such compounds or pharmaceuticalcompositions.

In one aspect, the present application discloses a compound, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound, said compound having the general structure shown in Formula I:

wherein:

-   -   R¹ represents alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,        arylalkenyl, heteroaryl or heteroarylalkyl; and    -   R²-R⁴ independently represent alkyl;        with the exception of those compounds wherein:    -   R²-R⁴ each represent methyl; and    -   R¹ represents phenyl substituted by substituted alkoxycarbonyl,        substituted alkylcarbonyloxy, substituted sulfonylamino,        substituted carbonylamino, or unsubstituted or substituted        aminocarbonyl;        and excluding the following compounds:

-   1,3,3-trimethyl-6-[(phenylmethyl)sulphonyl]-6-azabicyclo[3.2.1]octane;

-   6-[(3,4-difluorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(4-aminophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   1,3,3-trimethyl-6-[[4-(5-phenyl-2-oxazolyl)phenyl]sulfonyl]-6-azabicyclo[3.2.1]octane;

-   6-[(2-methyl-5-tert-butylphenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;

-   6-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[[5-2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenoxy]-2-hydroxyphenyl]sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   1,3,3-trimethyl-6-[[5-[2-[[2-(2-oxo-1-imidazolidinyl)ethyl]amino]-4-pyrimidinyl]-2-thienyl]sulfonyl]-6-azabicyclo[3.2.1]octane;

-   6-[(4-ethoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   1,3,3-trimethyl-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-6-azabicyclo[3.2.1]octane;

-   6-[(2,3-dichlorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   3-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic    acid;

-   3-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic    acid methyl ester;

-   1,3,3-trimethyl-6-[(3-nitrophenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;

-   4-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic    acid;

-   1,3,3-trimethyl-6-[(2,3,5,6-tetramethylphenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;

-   1,3,3-trimethyl-6-[(2-nitrophenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;

-   6-[(4-acetylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(2,5-dimethylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(4-methoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(5-bromo-2-ethoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(2,5-dibromophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(2,4-difluorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   6-[(2,5-dichlorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;

-   1,3,3-trimethyl-6-phenylsulfonyl-6-azabicyclo[3.2.1]octane;

-   6-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)benzo[d]oxazol-2(3H)-one;

-   6-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)benzo[cd]indol-2(1H)-one;

-   3-((1R,5S)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)-1H-pyrazolo[3,4-b]pyridine;

-   2,2,2-trifluoro-1-(8-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;

-   6-[(4-tert-butylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;    and

-   6-[(3-aminophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane.

The compounds of Formula I, including those excepted and excluded, aswell as salts, solvates, esters and prodrugs thereof, are inhibitors of11β-hydroxysteroid dehydrogenase type-I, and can be used in thetreatment of metabolic syndromes, obesity, obesity-related disorders,hypertension, atherosclerosis, lipid disorders, type-II diabetes,insulin resistance, pancreatitis and associated conditions.

Alternatively, the present invention provides for a method for treatinga metabolic syndrome in a patient in need thereof which comprisesadministering to said patient a therapeutically effective amount of atleast one compound of the Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof;

-   wherein:    -   R¹ represents alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,        arylalkenyl, heteroaryl or heteroarylalkyl; and    -   R²-R⁴ independently represent alkyl.

A further embodiment of the present invention is a method for treatingobesity or an obesity-related disorder in a patient in need thereofwhich comprises administering to said patient a therapeuticallyeffective amount of at least one compound of the Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof;

-   wherein:    -   R¹ represents alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,        arylalkenyl, heteroaryl or heteroarylalkyl; and    -   R²-R⁴ independently represent alkyl.

Another embodiment of the present invention is a method for treatingtype-II diabetes in a patient in need thereof which comprisesadministering to said patient a therapeutically effective amount of atleast one compound of the Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof;

-   wherein:    -   R¹ represents alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,        arylalkenyl, heteroaryl or heteroarylalkyl; and    -   R²-R⁴ independently represent alkyl.

Another embodiment of the present invention is a method for treatingatherosclerosis in a patient in need thereof which comprisesadministering to said patient a therapeutically effective amount of atleast one compound of the Formula I:

or a pharmaceutically acceptable salt, solvate, ester or prodrugthereof;

-   wherein:    -   R¹ represents alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,        arylalkenyl, heteroaryl or heteroarylalkyl; and    -   R²-R⁴ independently represent alkyl.

DETAILED DESCRIPTION

In one embodiment, the present invention discloses certain heterocycliccompounds which are represented by structural Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug thereof,wherein the various moieties are as described above.

In another embodiment, the present invention embodies compounds of theFormula I, as well as salts, solvates, esters and prodrugs thereof,wherein:

-   -   R¹ represents phenyl, naphthyl, benzyl, stryryl, furanyl,        thienyl, pyrazolyl, pyridyl, oxazolyl, benzothienyl or        benzooxadiazolyl, each of which is optionally substituted by one        or more substituents selected from the group consisting of        alkyl, halogen, alkoxy, alkylcarbonyl, alkylsulphonyl, cyano,        nitro, aryl, heteroaryl, aryloxy, carboxyl, alkoxycarbonylalkyl,        cycloalkyl and morpholino; and    -   R²-R⁴ each represent alkyl.

Table 1 shows structures of representative compounds of this invention.The table and the compounds therein are not intended, nor should they beconstrued, to limit this invention in any manner whatsoever.

TABLE 1 COMPOUND NO. STRUCTURE 1

2

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As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, oxime (e.g., ═N—OH),—NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, carboxy and —C(O)O-alkyl. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl andt-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl. aryl, cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. “Heteroaryl”may also include a heteroaryl as defined above fused to an aryl asdefined above. Non-limiting examples of suitable heteroaryls includepyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (includingN-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, acyl,aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, oxo, —C(═N—CN)—NH₂, —C(═NH)—NH₂, —C(═NH)—NH(alkyl),oxime (e.g., ═N—OH), Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂ ⁻ and—SO₂NY₁Y₂, wherein Y₁ and V₂ can be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, cycloalkyl, and aralkyl. “Ring system substituent” may also mean asingle moiety which simultaneously replaces two available hydrogens ontwo adjacent carbon atoms (one H on each carbon) on a ring system.Examples of such moiety are methylene dioxy, ethylenedioxy, —C(CH₃)₂—and the like which form moieties such as, for example:

In a preferred embodiment, R¹ represents a phenyl group optionallysubstituted with one or more ring substituents. In one especiallypreferred embodiment, a ring substituent is bonded at the para-positionof the phenyl ring. In another especially preferred embodiment, the ringsubstituent is a branched alkyl group. In another especially preferredembodiment, the ring substituent contains a hydroxyl group or an etherlinkage.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. Any —NH in a heterocyclylring may exist protected such as, for example, as an —N(Boc), —N(CBz),—N(Tos) group and the like; such protections are also considered part ofthis invention. The heterocyclyl can be optionally substituted by one ormore “ring system substituents” which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, lactam, lactone, and the like. “Heterocyclyl” mayalso mean a single moiety (e.g., carbonyl) which simultaneously replacestwo available hydrogens on the same carbon atom on a ring system.Example of such moiety is pyrrolidone:

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 10 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”may also mean a single moiety (e.g., carbonyl) which simultaneouslyreplaces two available hydrogens on the same carbon atom on a ringsystem. Example of such moiety is pyrrolidinone:

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5.

It should also be noted that tautomeric forms such as, for example, themoieties:

are considered equivalent in certain embodiments of this invention.

“Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di(C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be inhibitorsof 11β-hydroxysteroid dehydrogenase type I.

The term “obesity” as used herein, refers to a patient being overweightand having a body mass index (BMI) of 25 or greater. In one embodiment,an obese patient has a BMI of 25 or greater. In another embodiment, anobese patient has a BMI from 25 to 30. In another embodiment, an obesepatient has a BMI greater than 30. In still another embodiment, an obesepatient has a BMI greater than 40.

The term “obesity-related disorder” as used herein refers to: (i)disorders which result from a patient having a BMI of 25 or greater; and(ii) eating disorders and other disorders associated with excessive foodintake. Non-limiting examples of an obesity-related disorder includeedema, shortness of breath, sleep apnea, skin disorders and high bloodpressure.

The term “metabolic syndrome” as used herein, refers to a set of riskfactors that make a patient more susceptible to cardiovascular diseaseand/or type 2 diabetes. A patient is said to have metabolic syndrome ifthe patient has one or more of the following five risk factors:

-   -   1) central/abdominal obesity as measured by a waist        circumference of greater than 40 inches in a male and greater        than 35 inches in a female;    -   2) a fasting triglyceride level of greater than or equal to 150        mg/dL;    -   3) an HDL cholesterol level in a male of less than 40 mg/dL or        in a female of less than 50 mg/dL;    -   4) blood pressure greater than or equal to 130/85 mm Hg; and    -   5) a fasting glucose level of greater than or equal to 110        mg/dL.

A preferred dosage is about 0.001 to 5 mg/kg of body weight/day of thecompound of Formula I. An especially preferred dosage is about 0.01 to 5mg/kg of body weight/day of a compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound.

In one embodiment, the present invention provides methods for treating aCondition in a patient, the method comprising administering to thepatient one or more compounds of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof and at least one additionaltherapeutic agent that is not a compound of Formula I, wherein theamounts administered are together effective to treat or prevent aCondition.

Non-limiting examples of additional therapeutic agents useful in thepresent methods for treating or preventing a Condition include,anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, cholesterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer protein (CETP) inhibitors, low-denisitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols, fatty acid esters of plant stanols, or anycombination of two or more of these additional therapeutic agents.

Non-limiting examples of anti-obesity agents useful in the presentmethods for treating a Condition include CB1 antagonists or inverseagonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists,MCH receptor antagonists, histamine H₃ receptor antagonists or inverseagonists, metabolic rate enhancers, nutrient absorption inhibitors,leptin, appetite suppressants and lipase inhibitors.

Non-limiting examples of appetite suppressant agents useful in thepresent methods for treating or preventing a Condition includecannabinoid receptor 1 (CB₁) antagonists or inverse agonists (e.g.,rimonabant); Neuropeptide Y (NPY1, NPY2, NPY4 and NPY5) antagonists;metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g.,2-methyl-6-(phenylethynyl)-pyridine and3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine); melanin-concentratinghormone receptor (MCH1 R and MCH2R) antagonists; melanocortin receptoragonists (e.g., Melanotan-II and Mc4r agonists); serotonin uptakeinhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT)transport inhibitors (e.g., paroxetine, fluoxetine, fenfluramine,fluvoxamine, sertaline and imipramine); norepinephrine (NE) transporterinhibitors (e.g., desipramine, talsupram and nomifensine); ghrelinantagonists; leptin or derivatives thereof; opioid antagonists (e.g.,nalmefene, 3-methoxynaltrexone, naloxone and nalterxone); orexinantagonists; bombesin receptor subtype 3 (BRS3) agonists;Cholecystokinin-A (CCK-A) agonists; ciliary neurotrophic factor (CNTF)or derivatives thereof (e.g.; butabindide and axokine); monoaminereuptake inhibitors (e.g., sibutramine); glucagon-like peptide 1 (GLP-1)agonists; topiramate; and phytopharm compound 57.

Non-limiting examples of metabolic rate enhancers useful in the presentmethods for treating or preventing a Condition include acetyl-CoAcarboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 (133)agonists; diacylglycerol acyltransferase inhibitors (DGAT1 and DGAT2);fatty acid synthase (FAS) inhibitors (e.g., Cerulenin);phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline,zaprinast, sildenafil, aminone, milrinone, cilostamide, rolipram andcilomilast); thyroid hormone β agonists; uncoupling protein activators(UCP-1, 2 or 3) (e.g., phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acidand retinoic acid); acyl-estrogens (e.g., oleoyl-estrone);glucocorticoid antagonists; 11-beta hydroxy steroid dehydrogenase type 1(11β HSD-1) inhibitors; melanocortin-3 receptor (Mc3r) agonists; andstearoyl-CoA desaturase-1 (SCD-1) compounds.

Non-limiting examples of nutrient absorption inhibitors useful in thepresent methods for treating or preventing a Condition include lipaseinhibitors (e.g., orlistat, lipstatin, tetrahydrolipstatin, teasaponinand diethylumbelliferyl phosphate); fatty acid transporter inhibitors;dicarboxylate transporter inhibitors; glucose transporter inhibitors;and phosphate transporter inhibitors.

Non-limiting examples of cholesterol biosynthesis inhibitors useful inthe present methods for treating or preventing a Condition includeHMG-CoA reductase inhibitors, squalene synthase inhibitors, squaleneepoxidase inhibitors and mixtures thereof.

Non-limiting examples of cholesterol absorption inhibitors useful in thepresent methods for treating or preventing a Condition include ezetimibeand other compounds suitable for the same purpose. In one embodiment,the cholesterol absorption inhibitor is ezetimibe.

HMG-CoA reductase inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, statins suchas lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin,cerivastatin, CI-981, resuvastatin, rivastatin, pitavastatin,rosuvastatin or L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid).

Squalene synthesis inhibitors useful in the present methods for treatingor preventing a Condition include, but are not limited to, squalenesynthetase inhibitors; squalestatin 1; and squalene epoxidaseinhibitors, such as NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride).

Bile acid sequestrants useful in the present methods for treating orpreventing a Condition include, but are not limited to, cholestyramine(a styrene-divinylbenzene copolymer containing quaternary ammoniumcationic groups capable of binding bile acids, such as QUESTRAN® orQUESTRAN LIGHT® cholestyramine which are available from Bristol-MyersSquibb), colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo), water soluble derivativessuch as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insolublequaternized polystyrenes, saponins and mixtures thereof. Suitableinorganic cholesterol sequestrants include bismuth salicylate plusmoritmorillonite clay, aluminum hydroxide and calcium carbonateantacids.

Probucol derivatives useful in the present methods for treating orpreventing a Condition include, but are not limited to, AGI-1067 andothers disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250.

IBAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, benzothiepines such astherapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine1,1-dioxide structure such as are disclosed in International PublicationNo. WO 00/38727.

Nicotinic acid receptor agonists useful in the present methods fortreating or preventing a Condition include, but are not limited to,those having a pyridine-3-carboxylate structure or apyrazine-2-carboxylate structure, including acid forms, salts, esters,zwitterions and tautomers, where available. Other examples of nicotinicacid receptor agonists useful in the present methods include nicotinicacid, niceritrol, nicofuranose and acipimox. An example of a suitablenicotinic acid product is NIASPAN® (niacin extended-release tablets)which are available from Kos Pharmaceuticals, Inc. (Cranbury, N.J.).

ACAT inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, avasimibe, HL-004,lecimibide and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]-methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs 2000 July; 60(1); 55-93, whichis incorporated by reference herein.

CETP inhibitors useful in the present methods for treating or preventinga Condition include, but are not limited to, those disclosed inInternational Publication No. WO 00/38721 and U.S. Pat. No. 6,147,090,which are incorporated herein by reference.

LDL-receptor activators useful in the present methods for treating orpreventing a Condition include, but are not limited to, include HOE-402,an imidazolidinyl-pyrimidine derivative that directly stimulates LDLreceptor activity. See M. Huettinger et al., “Hypolipidemic activity ofHOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”,Arterioscler. Thromb. 1993; 13:1005-12.

Natural water-soluble fibers useful in the present methods for treatingor preventing a Condition include, but are not limited to, psyllium,guar, oat and pectin.

Fatty acid esters of plant stanols useful in the present methods fortreating or preventing a Condition include, but are not limited to, thesitostanol ester used in BENECOL® margarine.

Non-limiting examples of antidiabetic agents useful in the presentmethods for treating a Condition include insulin sensitizers,β-glucosidase inhibitors, DPP-IV inhibitors, insulin secretagogues,hepatic glucose output lowering compounds, antihypertensive agents,sodium glucose uptake transporter 2 (SGLT-2) inhibitors, insulin andinsulin-containing compositions, and anti-obesity agents as set forthabove.

In one embodiment, the antidiabetic agent is an insulin secretagogue. Inone embodiment, the insulin secretagogue is a sulfonylurea.

Non-limiting examples of sulfonylureas useful in the present methodsinclude glipizide, tolbutamide, glyburide, glimepiride, chlorpropamide,acetohexamide, gliamilide, gliclazide, gliquidone, glibenclamide andtolazamide.

In another embodiment, the insulin secretagogue is a meglitinide.

Non-limiting examples of meglitinides useful in the present methods fortreating a Condition include repaglinide, mitiglinide, and nateglinide.

In still another embodiment, the insulin secretagogue is GLP-1 or aGLP-1 mimetic.

Non-limiting examples of GLP-1 mimetics useful in the present methodsinclude Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem,Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (ZealandPharmaceuticals), and compounds disclosed in International PublicationNo. WO 00/07617.

Other non-limiting examples of insulin secretagogues useful in thepresent methods include exendin, GIP and secretin.

In another embodiment, the antidiabetic agent is an insulin sensitizer.

Non-limiting examples of insulin sensitizers useful in the presentmethods include PPAR activators or agonists, such as troglitazone,rosiglitazone, pioglitazone and englitazone; biguanidines such asmetformin and phenformin; PTP-1 B inhibitors; and glucokinaseactivators.

In another embodiment, the antidiabetic agent is a β-Glucosidaseinhibitor.

Non-limiting examples of β-Glucosidase inhibitors useful the presentmethods include miglitol, acarbose, and voglibose.

In another embodiment, the antidiabetic agent is an hepatic glucoseoutput lowering agent.

Non-limiting examples of hepatic glucose output lowering agents usefulin the present methods include Glucophage and Glucophage XR.

In yet another embodiment, the antidiabetic agent is insulin, includingall formualtions of insulin, such as long acting and short acting formsof insulin.

Non-limiting examples of orally administrable insulin and insulincontaining compositions include AL-401 from Autoimmune, and thecompositions disclosed in U.S. Pat. Nos. 4,579,730; 4,849,405;4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632;6,191,105; and International Publication No. WO 85/05029, each of whichis incorporated herein by reference.

In another embodiment, the antidiabetic agent is a DPP-IV inhibitor.

Non-limiting examples of DPP-IV inhibitors useful in the present methodsinclude sitagliptin, saxagliptin, denagliptin, vildagliptin, alogliptin,alogliptin benzoate, Galvus (Novartis), ABT-279 and ABT-341 (Abbott),ALS-2-0426 (Alantos), ARI-2243 (Arisaph), BI-A and BI-B (BoehringerIngelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer) andRO-0730699 (Roche).

In a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.

Non-limiting examples of SGLT-2 inhibitors useful in the present methodsinclude dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) andT-1095 (Tanabe Seiyaku).

Non-limiting examples of antihypertensive agents useful in the presentmethods for treating a Condition include β-blockers and calcium channelblockers (for example diltiazem, verapamil, nifedipine, amlopidine, andmybefradil), ACE inhibitors (for example captopril, lisinopril,enalapril, spirapril, ceranopril, zefenopril, fosinopril, cilazopril,and quinapril), AT-1 receptor antagonists (for example losartan,irbesartan, and valsartan), renin inhibitors and endothelin receptorantagonists (for example sitaxsentan).

In one embodiment, the antidiabetic agent is an agent that slows orblocks the breakdown of starches and certain sugars.

Non-limiting examples of antidiabetic agents that slow or block thebreakdown of starches and certain sugars and are suitable for use in thecompositions and methods of the present invention includealpha-glucosidase inhibitors and certain peptides for increasing insulinproduction. Alpha-glucosidase inhibitors help the body to lower bloodsugar by delaying the digestion of ingested carbohydrates, therebyresulting in a smaller rise in blood glucose concentration followingmeals. Non-limiting examples of suitable alpha-glucosidase inhibitorsinclude acarbose; miglitol; camiglibose; certain polyamines as disclosedin WO 01/47528 (incorporated herein by reference); voglibose.Non-limiting examples of suitable peptides for increasing insulinproduction including amlintide (CAS Reg. No. 122384-88-7 from Amylin;pramlintide, exendin, certain compounds having Glucagon-like peptide-1(GLP-1) agonistic activity as disclosed in International Publication No.WO 00/07617.

Other specific additional therapeutic agents useful in the presentmethods for treating or preventing a Condition include, but are notlimited to, rimonabant, 2-methyl-6-(phenylethynyl)-pyridine,3[(2-methyl-1,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-II,dexfenfluramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine,sertaline, imipramine, desipramine, talsupram, nomifensine, leptin,nalmefene, 3-methoxynaltrexone, naloxone, nalterxone, butabindide,axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin,theophylline, pentoxifylline, zaprinast, sildenafil, aminone, milrinone,cilostamide, rolipram, cilomilast, phytanic acid,4-[(E)-2-(5,6,7,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid,retinoic acid, oleoyl-estrone, orlistat, lipstatin, tetrahydrolipstatin,teasaponin and diethylumbelliferyl phosphate.

In one embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a compound of formula (I), anantidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a compound of formula (I) andan antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing diabetes comprise administering a compound of formula (I) andan anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing obesity comprise administering a compound of formula (I), anantidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a compound of formula (I) andan antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing obesity comprise administering a compound of formula (I) andan anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a compound offormula (I) and one or more additional therapeutic agents selected from:anti-obesity agents, antidiabetic agents, any agent useful for treatingmetabolic syndrome, any agent useful for treating a cardiovasculardisease, cholesterol biosynthesis inhibitors, sterol absorptioninhibitors, bile acid sequestrants, probucol derivatives, IBATinhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors,cholesteryl ester transfer protein (CETP) inhibitors, low-denisitylipoprotein (LDL) activators, fish oil, water-soluble fibers, plantsterols, plant stanols and fatty acid esters of plant stanols.

In one embodiment, the additional therapeutic agent is a cholesterolbiosynthesis inhibitor. In another embodiment, the cholesterolbiosynthesis inhibitor is an HMG-CoA reductase inhibitor. In anotherembodiment, the HMG-CoA reductase inhibitor is a statin. In anotherembodiment, the statin is lovastatin, pravastatin, simvastatin oratorvastatin.

In one embodiment, the additional therapeutic agent is a cholesterolabsorption inhibitor. In another embodiment, the cholesterol absorptioninhibitor is ezetimibe. In another embodiment, the cholesterolabsorption inhibitor is a squalene synthetase inhibitor. In anotherembodiment, the cholesterol absorption inhibitor is a squalene epoxidaseinhibitor.

In one embodiment, the additional therapeutic agent comprises acholesterol absorption inhibitor and a cholesterol biosynthesisinhibitor. In another embodiment, the additional therapeutic agentcomprises a cholesterol absorption inhibitor and a statin. In anotherembodiment, the additional therapeutic agent comprises ezetimibe and astatin. In another embodiment, the additional therapeutic agentcomprises ezetimibe and simvastatin.

In one embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a compound offormula (I), an antidiabetic agent and/or an antiobesity agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a compound offormula (I) and an antidiabetic agent.

In another embodiment, the present combination therapies for treating orpreventing metabolic syndrome comprise administering a compound offormula (I) and an anti-obesity agent.

In one embodiment, the present combination therapies for treating orpreventing a cardiovascular disease comprise administering one or morecompounds of formula (I), and an additional agent useful for treating orpreventing a cardiovascular disease.

When administering a combination therapy to a patient in need of suchadministration, the therapeutic agents in the combination, or apharmaceutical composition or compositions comprising the therapeuticagents, may be administered in any order such as, for example,sequentially, concurrently, together, simultaneously and the like. Theamounts of the various actives in such combination therapy may bedifferent amounts (different dosage amounts) or same amounts (samedosage amounts).

In one embodiment, the one or more compounds of Formula I areadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the one or more compounds of Formula I and theadditional therapeutic agent(s) are administered in doses commonlyemployed when such agents are used as monotherapy for treating aCondition.

In another embodiment, the one or more compounds of Formula I and theadditional therapeutic agent(s) are administered in doses lower than thedoses commonly employed when such agents are used as monotherapy fortreating a Condition.

In still another embodiment, the one or more compounds of Formula I andthe additional therapeutic agent(s) act synergistically and areadministered in doses lower than the doses commonly employed when suchagents are used as monotherapy for treating a Condition.

In one embodiment, the one or more compounds of Formula I and theadditional therapeutic agent(s) are present in the same composition. Inone embodiment, this composition is suitable for oral administration. Inanother embodiment, this composition is suitable for intravenousadministration.

The one or more compounds of Formula I and the additional therapeuticagent(s) can act additively or synergistically. A synergisticcombination may allow the use of lower dosages of one or more agentsand/or less frequent administration of one or more agents of acombination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of the therapy without reducingthe efficacy of the therapy.

In one embodiment, the administration of one or more compounds ofFormula I and the additional therapeutic agent(s) may inhibit theresistance of a Condition to these agents.

In one embodiment, when the patient is treated for diabetes or adiabetic complication, the additional therapeutic agent is anantidiabetic agent which is not a compound of Formula I. In anotherembodiment, the additional therapeutic agent is an agent useful forreducing any potential side effect of a compound of Formula I. Suchpotential side effects include, but are not limited to, nausea,vomiting, headache, fever, lethargy, muscle aches, diarrhea, generalpain, and pain at an injection site.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

The invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug of said compound and at leastone pharmaceutically acceptable carrier.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium state, talc, sugar or lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration. Examples of pharmaceutically acceptablecarriers and methods of manufacture for various compositions may befound in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^(th)Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.

The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitable sized unit dosescontaining appropriate quantities of the active component, e.g. aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I, or apharmaceutically acceptable salt, solvate, ester or prodrug of saidcompound and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable salt,solvate, ester or prodrug of said compound and an amount of at least onetherapeutic agent listed above, wherein the amounts of the two or moreingredients result in a desired therapeutic effect.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Where NMR data are presented, ¹H spectra were obtained on either aVariant VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHZ), VarianMercury VX-400 (400 MHz), or Bruker-Biospin AV-500(500 MHz), and arereported as ppm with number of protons and multiplicities indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and C18 column,10-95% CH₃CN—H₂O (with 0.05% TFA) gradient. The observed parent ion isgiven.

The following solvents and reagents may be referred to by theirabbreviations in parenthesis:

-   Me=methyl-   Et=ethyl-   Pr=propyl-   Bu=butyl-   Ph=phenyl-   Ac=acetyl-   μl=microliters-   AcOEt or EtOAc=ethyl acetate-   AcOH or HOAc=acetic acid-   ACN=acetonitrile-   atm=atmosphere-   Boc or BOC=tert-butoxycarbonyl-   DCE=dichloroethane-   DCM or CH₂Cl₂=dichloromethane-   DIPEA=diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   DMF=dimethylformamide-   DMS=dimethylsulfide-   DMSO=dimethyl sulfoxide-   EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimine-   Fmoc or FMOC=9-fluorenylmethoxycarbonyl-   g=grams-   h=hour-   hal=halogen-   HOBt=1-hydroxybenzotriazole-   LAH=lithium aluminum hydride-   LCMS=liquid chromatography mass spectrometry-   min=minute-   mg=milligrams-   mL=milliliters-   mmol=millimoles-   MCPBA=3-chloroperoxybenzoic acid-   MeOH=methanol-   MS=mass spectrometry-   NMR=nuclear magnetic resonance spectroscopy-   RT or rt=room temperature (ambient, about 25° C.)-   TEA or Et₃N=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   TMS=trimethylsilyl-   Tr=triphenylmethyl

EXAMPLES

The compounds of this invention can be prepared as generally describedin the Preparation Scheme, and the following examples.

Preparation Scheme

Polystyrene DIEA resin (47 mg, 0.045 mmol) was added to 40-wells of adeep well polypropylene microtiter plate followed by a MeCN/THF (2:1)stock solution (1 mL) of 1,3,3-trimethyl-6-azabicyclo-[3.2.1]octane X(8.0 mg, 0.05 mmol). Then 0.5 M stock solutions of each of theindividual sulfonyl chlorides (R₁₋₄₅SO₂Cl) (0.210 mL, 0.10 mmol) wereadded to the wells, which was then sealed and shaken at 25° C. for 20 h.The solutions were filtered thru a polypropylene frit into a 2^(nd)microtiter plate containing polystyrene isocyanate resin (103 mg, 3equivalents, 1.52 mmol/g) and polystyrene trisamine resin (74 mg, 6equivalents, 4.23 mmol/g). After the top plate was washed with MeCN (0.5mL), the plate was removed, the bottom microtiter plate sealed andshaken at 25° C. for 16 hrs. Then the solutions were filtered thru apolypropylene frit into a 96-well collection plate. The wells of the topplate were then washed with MeCN (2×0.5 mL), and the plate removed. Thenthe resultant solutions in the collection plate were transferred intovials and the solvents removed in vacuo via a SpeedVac to provide thesulfonamides.

Using this Preparation Scheme, the inventive compounds can be prepared.

Compound No. 1

To a solution of 1,3,3-trimethyl-6-azabicyclo-[3.2.1]octane (0.06 mL,0.33 mmol) in CH₂Cl₂ (3.3 mL) was added diisopropylethyl amine (0.17 mL,0.99 mmol) followed by the sulfonyl chloride (0.49 mmol). The reactionwas stirred at RT under nitrogen for 21 h after which it was quenchedwith 1 N HCl and extracted with CH₂Cl₂. The organics were dried overMgSO₄, filtered and concentrated to give crude material. Purification byPTLC (15% EtOAc/hexanes) afforded the desired sulfonamide Compound No. 1(115 mg, 100%).

Compound Nos. 2, 3, 47, 48, 51-67, 76-81 andN-(4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)phenyl)acetamide,a compound purchased from TRIPOS, were prepared using commerciallyavailable sulfonyl chlorides in a similar manner as described for thesynthesis of Compound No. 1.Yields ranged from 40 to 100%.

Separation of Compound No. 23

Compound No. 23 was prepared in the same manner as Compound No. 1.

About 90 mg of Compound No. 23 was dissolved in 5% IPA/hexanes (1.2 mL)and injected onto a chiralpak AS prep HPLC column (5 cm×50 cm) andeluted with 5% IPA/hexanes at 100 mL/min. Detection at 254 nm. 45 mg ofCompound No. 54 (isomer 1, retention time=30.1 min) and 45 mg of amixture of isomer 1 and 2 were obtained. The mixture (45 mg) wasdissolved in 25% IPA/hexanes and injected onto the chiralpak AS prepcolumn for the second time and eluted with 3% IPA/hexanes at 50 mL/min.20.5 mg of Compound No. 55 (isomer 2, retention time=−67 min) wasobtained.

Separation of Compound No. 16

Compound No. 16 was prepared in the same manner as Compound No. 1.

About 240 mg of Compound No. 16 was dissolved in 5% IPA/hexanes (1.2 mL)and injected onto a chiralpak AS prep HPLC column (5 cm×50 cm) andeluted with 15% IPA/hexanes at 75 mL/min. Detection at 254 nm. 81.3 mgof Compound No. 67 (isomer 1, retention time=46.4 min) and 102 mg of amixture of isomer 1 and 2 were obtained. The mixture (102 mg) wasdissolved in 25% IPA/hexanes and injected onto the chiralpak AS prepcolumn for the second time and eluted with 15% IPA/hexanes at 50 mL/min.44.0 mg of Compound No. 66 (isomer 2, retention time=86.9 min) wasobtained.

Reduction of Compound No. 67

To a solution of Compound No. 67 (0.039 g, 0.12 mmol) in MeOH (1.5 mL)was added sodium borohydride (0.012 g, 0.32 mmol) at 0° C. in (icebath). After stirring at room temperature for 1 h, the reaction wasquenched with saturated ammonium chloride solution and extracted withCH₂Cl₂. The organic fractions were combined, dried over MgSO₄, filtered,and concentrated to give the crude material. Purification by PTLC (2%MeOH/CH₂Cl₂) yielded the desired reduction product Intermediate A as amixture of enantiomers (33 mg, 85%).

Separation of Compound No. 67

About 18 mg of Intermediate A from the previous example was dissolved in20% IPA/hexanes (1.0 mL) and injected onto a chiralpak AD semi-prep HPLCcolumn and eluted with 10% IPA/hexanes at 10 mL/min. Detection at 254nm. 7.9 mg of Compound No. 73 (isomer 1, retention time=19.1 min) and7.3 mg of Compound No. 72 (isomer 2, retention time=22.6 min) wereobtained.

Separation of Compound No. 66

Intermediate B was prepared from Compound No. 66 in the same manner asIntermediate A was prepared from Compound No. 67. Compound No. 71(isomer 3, retention time=18.8 min, 95%) and Compound No. 70 (isomer 4,retention time=22.8 min, 5%) were prepared in the same manner asCompound No. 72 and Compound No. 73.

Preparation of Compound No. 81

To a solution of Compound No. 67 (34 mg, 0.10 mmol) in THF (2 mL) wasadded methylmagnesium bromide (3M in ether, 0.18 mL, 0.40 mmol). Thereaction was stirred at room temperature for 1.5 h after which it wasquenched with saturated ammonium chloride solution and extracted withCH₂Cl₂. The organic fraction was dried (MgSO₄), filtered, andconcentrated to give a crude material. Purification by preparative TLC(25% EtOAc/Hexanes) afforded the desired compound Compound No. 81 (20.9mg, 60%).

Compound No. 80 was prepared in the same manner as Compound No. 81 fromCompound No. 66.

Preparation of Compound No. 79

NaH (6 mg, 0.25 mmol) was added to a solution of Compound No. 81 (18.2mg, 0.050 mmol) in DMF (1 mL) at 0° C. After 15 min., iodomethane (0.01mL, 0.10 mmol) was added and the reaction was warmed to roomtemperature. After 1.75 hours, the reaction was quenched with water andextracted with EtOAc. The combined organics were washed with water,dried over MgSO₄, filtered and concentrated to give the crude material.Purification by PTLC (20% EtOAc/Hexanes) yielded the Compound No. 79(9.0 mg, 48%).

Compound No. 78 was prepared in a similar manner as Compound No. 79 fromCompound No. 80.

In vitro 11β-HSD1 activity assayPreparation of 11β-HSD1 membranes

Human 11β-HSD1 with N-terminal myc tag was expressed in Sf9 cells usingbaculovirus Bac-to-Bac expression system (Invitrogen) according tomanufacturer's instructions. Cells were harvested three days afterinfection and washed in PBS before frozen. To make membranes, the cellswere resuspended in buffer A (20 mM Tris-HCl, pH7.4, 100 mM NaCl, 2 mMEDTA, 2 mM EGTA and Complete™ protease inhibitor tablets (RocheMolecular Biochemicals)), and lysed in a nitrogen bomb at 900 psi. Thecell lysate was centrifuged at 600 g for 10 min to remove nuclei andlarge cell debris. The supernatant was centrifuged at 100,000 g for 1hr. The membrane pellet was resuspended in buffer A, flash-frozen inliquid nitrogen and stored at −70° C. before use.

Measurement of 11β-HSD1 activity

11β-HSD1 enzymatic activity was measured in a 50 μl reaction containing20 mM NaPO₄ pH 7.5, 0.1 mM MgCl₂, 3 mM NADPH (prepared fresh daily), 125nM ³H-cortisone (American Radiochemicals) and 0.5 μg membrane. Thereaction was incubated at room temperature for 1 hr before it wasstopped by addition of 50 μM buffer containing 20 mM NaPO₄ pH 7.5, 30 μM18β-glycyrrhetinic acid, 1 μg/ml monoclonal anti-cortisol antibody(Biosource) and 2 mg/ml anti-mouse antibody coated scintillationproximity assay (SPA) beads (Amersham Bioscience). The mixture wasincubated at room temperature for 2 hrs with vigorous shaking andanalyzed on TopCount scintillation counter.

Compounds according to the present invention showed activity against11β-HSD1 in this assay.

In Vivo Screen for Inhibition of 11β-HSD-1

Lean male C57BI/6N mice were orally dosed with a solution ofdexamethasone (0.5 mg/kg) and test agent or vehicle (20% HPβCD (10ml/kg)). One hour later, cortisone was administered (1 mg/kg sc insesame oil). One hour after cortisone administration, animals wereeuthanized for blood collection, and plasma cortisol levels weredetermined with a commercially available ELISA.

Compounds according to the present invention inhibited 11β-HSD1 in thisscreen.

Table 2 shows 11β-HSD-1 activity of representative compounds of thisinvention. The table and the compounds therein are not intended, norshould they be construed, to limit this invention in any mannerwhatsoever.

TABLE 2 Mouse cort. Human Mouse challenge 11β-HSD-1 11β-HSD-1 % ICompound No. IC₅₀ (nM) IC₅₀ (nM) @ 30 mpk 29 5714 13266 76 126 1819 102509 3167 39 268 686 12 1415 28195 13 407 2483 5 3006 18247 6 247 670 43392 7926 74 5714 11136 75 126 5937 32 2509 3167 48 268 686 3 407 187564 340 217 61 415 165 25 169 364 63 111 305 62 96 309 9 190 420 17 67127 1 31 71 30 23 28 19 26 65 372 950 68 55 112 16 139 732 44 16 67 6345 19 27 16 46 10 87 50 7 43 43 49 23 11 19 69 30 68

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

What is claimed is:
 1. A compound represented by the structural FormulaI:

or a pharmaceutically acceptable salt of said compound, wherein: R¹represents phenyl, naphthyl, benzyl, stryryl, furanyl, thienyl,pyrazolyl, pyridyl, oxazolyl, benzothienyl or benzooxadiazolyl, each ofwhich is optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halogen, alkoxy, alkylcarbonyl,alkylsulphonyl, cyano, nitro, aryl, heteroaryl, aryloxy, carboxyl,alkoxycarbonylalkyl, cycloalkyl and morpholino; and R²-R⁴ independentlyrepresent alkyl; with the exception of those compounds wherein: R²-R⁴each represent methyl; and R¹ represents phenyl substituted bysubstituted alkoxycarbonyl, substituted alkylcarbonyloxy, substitutedsulfonylamino, substituted carbonylamino, or unsubstituted orsubstituted aminocarbonyl; and excluding the following compounds:1,3,3-trimethyl-6-[(phenylmethyl)sulphonyl]-6-azabicyclo[3.2.1]octane;6-[(3,4-difluorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(4-aminophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;1,3,3-trimethyl-6-[[4-(5-phenyl-2-oxazolyl)phenyl]sulfonyl]-6-azabicyclo[3.2.1]octane;6-[(2-methyl-5-tert-butylphenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;6-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[[5-2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenoxy]-2-hydroxyphenyl]sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;1,3,3-trimethyl-6-[[5-[2-[[2-(2-oxo-1-imidazolidinyl)ethyl]amino]-4-pyrimidinyl]-2-thienyl]sulfonyl]-6-azabicyclo[3.2.1]octane;6-[(4-ethoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;1,3,3-trimethyl-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-6-azabicyclo[3.2.1]octane;6-[(2,3-dichlorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;3-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic acid;3-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic acidmethyl ester;1,3,3-trimethyl-6-[(3-nitrophenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;4-[(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)sulfonyl]benzoic acid;1,3,3-trimethyl-6-[(2,3,5,6-tetramethylphenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;1,3,3-trimethyl-6-[(2-nitrophenyl)sulfonyl]-6-azabicyclo[3.2.1]octane;6-[(4-acetylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(2,5-dimethylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(4-methoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(5-bromo-2-ethoxyphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(2,5-dibromophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(2,4-difluorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;6-[(2,5-dichlorophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;1,3,3-trimethyl-6-phenylsulfonyl-6-azabicyclo[3.2.1]octane;6-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)benzo[d]oxazol-2(3H)-one;6-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)benzo[cd]indol-2(1H)-one;3-((1R,5S)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)-1H-pyrazolo[3,4-b]pyridine;2,2,2-trifluoro-1-(8-(1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-ylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone;6-[(4-tert-butylphenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane;and6-[(3-aminophenyl)sulfonyl]-1,3,3-trimethyl-6-azabicyclo[3.2.1]octane.2. A compound selected from the group consisting of:

an enantiomer thereof or a pharmaceutically acceptable salt thereof. 3.A pharmaceutical composition comprising at least one compound of claim1, or a pharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable carrier, adjuvant or vehicle.
 4. Apharmaceutical composition comprising at least one compound of claim 2,an enantiomer thereof or a pharmaceutically acceptable salt thereof andat least one pharmaceutically acceptable carrier, adjuvant or vehicle.